Increased Cathepsin S in Prdm1−/− dendritic cells alters T(FH) repertoire and contributes to lupus

Aberrant expansion of follicular helper T (T(FH)) cells occurs in lupus patients. An unanswered question is whether an altered T cell receptor (TCR) repertoire is associated with this expansion. Here, we demonstrate that Blimp-1 repressed expression of the cathepsin S gene (Ctss) which encodes a cysteine protease that cleaves invariant chain and produces antigenic peptides for MHC class II loading. The increased CTSS in dendritic cells (DCs) of female Prdm1 conditional knockout (CKO) mice altered antigen presentation to CD4(+) T cells. Analysis of V(β) CDR3s demonstrated a more diverse repertoire of T(FH) from female CKO mice. In vivo treatment of CKO mice with a CTSS inhibitor abrogated lupus-related phenotypes and reduced the diversity of the T(FH) TCR repertoire. Thus, Blimp-1 deficiency in DCs leads to a loss of appropriate regulation of Ctss expression in female mice thereby modulating antigen presentation and T(FH) repertoire to contribute to autoimmunity.